We propose to study peripheral mechanisms that underlie hyperalgesia induced by intradermal injection of the C-fiber excitotoxin capsaicin. In humans such injection produces burning pain with characteristics similar to neuropathic pain syndromes. To investigate our hypothesis that capsaicin-induced primary and secondary hyperalgesia depend on interactions between primary afferent neurons and sympathetic postganglionic neurons, we will use a model of capsaicin-induced hyperalgesia in the rat. First, we will perform behavioral experiments to characterized the time course and dose-dependence of capsaicin-induced primary and secondary hyperalgesia, and to determine if maintenance of the hyperalgesia depends on ongoing activity in primary afferents. We will also determine if capsaicin-evoked primary hyperalgesia is sympathetic-dependent. Second, electrophysiological studies of single dorsal root nerve fibers will examine changes in primary afferent activity during capsaicin- induced hyperalgesia and investigate the role of the sympathetic postganglionic neuron in these changes. We will inject local anesthetic into the skin to determine the extent to which secondary hyperalgesia depends on capsaicin-evoked activity that originates from the area of primary hyperalgesia. We will also determine the contribution of SPGN activity to the electrophysiological changes that accompany primary and secondary hyperalgesia with experiments in which peripheral sympathetics are ablated or stimulated. Third, electrophysiological and anatomical studies will determine if activity of sympathetic postganglionic neurons increases during capsaicin-induced hyperalgesia, and if small-diameter DRG neurons can stimulate such activity. Finally, we will perform behavioral, electrophysiological, and anatomical experiments to localize the site of sympatho-sensory interaction and to characterize its adrenergic pharmacology. The experiments will determine if the site of interaction occurs in the skin or dorsal root ganglion. If the experiments demonstrate that sympatho-sensory interaction occurs in the skin, receptor subtype antagonists will be injected in the skin in regions of primary and secondary hyperalgesia. These studies should provide novel information on the nature of sympatho- sensory interactions in a phenomenon that has numerous characteristics in common with neuropathic pain syndromes in humans. The results will elucidate the importance of primary afferent and sympathetic activity, nature and site of sympatho-sensory interaction, and the relative role of peripheral and central mechanisms in maintaining secondary hyperalgesia. This information will improve our understanding of pain mechanisms, sensory neurophysiology and peripheral sympathetic mechanisms.